AU680992B2

AU680992B2 - (4-(1,2-epoxycyclohexanyl) but-3-EN-1-ynyl) aromatic and heteroaromatic acids and derivatives having retinoid-like biological activity

Info

Publication number: AU680992B2
Application number: AU14308/95A
Authority: AU
Inventors: Richard L. Beard; Roshantha A. Chandraratna
Original assignee: Allergan Inc
Current assignee: Allergan Inc
Priority date: 1993-12-30
Filing date: 1994-12-07
Publication date: 1997-08-14
Anticipated expiration: 2014-12-07
Also published as: US5451605A; EP0737190A1; CA2180009A1; JPH09507226A; WO1995018120A1; AU1430895A

Description

~I I I I_ WO 95/18120 PCT/US94/13901 1 [4-(1,2-EPOXYCYCLOHEXANYL)BUT-3-EN-1-YNYL]AROMATIC AND HETEROAROMATIC ACIDS AND DERIVATIVES HAVING RETINOID-LIKE BIOLOGICAL ACTIVITY BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention is directed to novel compounds which have retinoid-like biological activity.

More specifically, a present invention relates to but-3-en-l-ynyl compounds which are substituted in the 1-position by an aromatic or heteroaromatic acid or ester, and on the 4-position by an alkyl-substituted 1,2-epoxycyclohexanyl moiety. The aromatic acid function may also be converted to an alcohol, aldehyde or ketone, or derivatives thereof, or may be reduced to

-CH

3 2. Related Art Compounds which have retinoid like activity are well known in the art, and are described in numerous United States and foreign patents and in scientific publications. It is generally known and accepted in the art that retinoid like activity is useful for treating animals of the mammalian species, including humans, for curing or alleviating the symptoms and conditions of numerous diseases and conditions. In other words, it is generally accepted in the art that pharmaceutical compositions having a retinoid like compound or compounds as the active ingredient are useful as regulators of cell proliferation and differentiation, and particularly as agents for treating dermatoses, such as acne, Darier's disease, psoriasis, icthyosis, eczema and atopic dermatitis, and for treating and preventing malignant hyperproliferative diseases such as epithelial cancer, -ii- 1 _II~ WO 95/18120 PCT/US94/13901 2 breast cancer, prostatic cancer, head and neck cancer and myeloid leukemias, for reversing and preventing atherosclerosis and restenosis resulting from neointimal hyperproliferation, for treating and preventing other non-malignant hyperproliferative diseases such as endometrial hyperplasia, benign prostatic hypertrophy, proliferative vitreal retinopathy and dysplasias, for treating autoimmune diseases and immunological disorders lupus erythematosus) for treating chronic inflammatory diseases such as pulmonary fibrosis, for treating and preventing diseases associated with lipid metabolism and transport such as dyslipidemias, for promoting wound healing, for treating dry eye syndrome and for reversing and preventing the effects of sun damage to skin.

United States Patent No. 4,739,098 describes but-3-en-l-ynyl compounds which are substituted in the 1-position by an aromatic acid or ester, and on the 4position by an alkyl-substituted -1-cyclohexene moiety.

United States Patent No. 4,927,947 describes but-3-en-l-ynyl compounds which are substituted in the 1-position by a heteroaromatic acid or ester, and on the 4-position by an alkyl-substituted -1-cyclohexene moiety. The compounds described in these patents have retinoid-like biological activity.

SUMMARY OF INVENTION The present invention relates to compounds of Formula 1 -s I I I-I WO 95/18120 PCT/US94/13901 3

R

1

R

2

R

6

Y-A-B

Rs- 0

R

3

R

4 Formula 1 where R. R7 are hydrogen, lower alkyl of 1 6 carbons, or halogen; Y is phenyl, pyridyl, furyl, thienyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl or oxazolyl; A is (CH 2 n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds; B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR 8

CONR

9

R

10

-CH

2

OH,

CH

2

OR

11

CH

2

OCOR

11 CHO, CH(OR 12 2

CHOR

1 30, -COR 14 CR14(OR12)2, or CR 14

OR

1 30, where R 8 is an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to carbons, or R 8 is phenyl or lower alkylphenyl, R 9 and

R

10 independently are hydrogen, an alkyl group of 1 to carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R 11 is lower alkyl, phenyl or lower alkylphenyl, R 12 is lower alkyl, R 13 is divalent alkyl radical of 2-5 carbons and Ri4 is an alkyl, cycloalkyl or alkenyl group containing 1 to carbons.

In a second aspect, this invention relates to the IL III -9DI I WO 95/18120 PCT/US94/13901 4 use of the compounds of Formula 1 as regulators for cell proliferation and differentiation, and particularly as agents for treating dermatoses, such as acne, Darier's disease, psoriasis, icthyosis, eczema, atopic dermatitis, and for treating and preventing malignant hyperproliferative diseases such as epithelial cancer, breast cancer, prostatic cancer, head and neck cancer and myeloid leukemias, for reversing and preventing artherosclerosis and restenosis resulting from neointimal hyperproliferation, for treating and preventing other non-malignant hyperproliferative diseases such as endometrial hyperplasia, benign prostatic hypertrophy, proliferative vitreal retinopathy and dysplasias, for treating autoimmune diseases and immunological disorders lupus erythematosus), for treating chronic inflammatory diseases such as pulmonary fibrosis, for treating and preventing diseases associated with lipid metabolism and transport such as dyslipidemias, for promoting wound healing, for treating dry eye syndrome and in reversing and preventing the effects of sun damage to skin.

This invention also relates to a pharmaceutical composition comprising a compound of Formula 1 in admixture with a pharmaceutically acceptable excipient.

In another aspect, this invention relates to the process for making a compound of Formula 1, which process comprises reacting a compound of Formula 2, where the symbols R i

R

7 Y, A and B are defined as in connection with Formula 1, with an epoxidizing agent; converting the ester of Formula 1 to an acid; and to prepare compounds in which A is (CH 2 n and n is homologating a compound of Formula 1 to increase the ~IIC~ asl~- I WO 95/18120 PCT/US94/13901 value of n, or converting an acid of Formula 1 to an ester; or converting an acid of Formula 1 to an amide; or reducing and acid of Formula 1 to an alcohol of aldehyde; or converting an alcohol of Formula 1 to an ether or ester; or converting an aldehyde of Formula 1 to an acetal.

R

2

R

6

Y-A-B

R

s 1

R

7

R

5

I

R

3

R

4 Formula 2 DETAILED DESCRIPTION OF THE INVENTION General Embodiments Definitions The term alkyl refers to and covers any and all groups which are known as normal alkyl, branched-chain alkyl and cycloalkyl. The term alkenyl refers to and covers normal alkenyl, branch chain alkenyl and cycloalkenyl groups having one or more sites of unsaturation. Lower alkyl means the above-defined broad definition of alkyl groups having 1 to 6 carbons, and as applicable, 3 to 6 carbons for branch chained and cyclo-alkyl groups. Lower alkenyl is defined similarly having 2 to 6 carbons for normal alkenyl, and 3 to 6 carbons for branch chained and cycloalkenyl groups.

L I k 11%1 WO 95/18120 PCT/US94/13901 6 The term "ester" as used here refers to and covers any compound falling within the definition of that term as classically used in organic chemistry. It includes organic and inorganic esters. Where B (of Formula 1) is -COOH, this term covers the products derived from treatment of this function with alcohols or thioalcohols preferably with aliphatic alcohols having 1-6 carbons. Where the ester is derived from compounds where B is -CH2OH, this term covers compounds derived from organic acids capable of forming esters including phosphorous based and sulfur based acids, or compounds of the formula -CH 2 0CORII where R1, is defined as above.

The term "amides" has the meaning classically accorded that term in organic chemistry. In this instance it includes the unsubstituted amides and all aliphatic and aromatic mono- and di- substituted amides.

A pharmaceutically acceptable salt may be prepared for any compounds in this invention having a functionality capable of forming such-salt, for example an acid functionality. A pharmaceutically acceptable salt is any salt which retains the activity of the parent compound and does not impart any deleterious or untoward effect on the subject to which it is administered and in the context in which it is administered.

Pharmaceutically acceptable salts may be derived from organic or inorganic bases. The salt may be a mono or polyvalent ion. Of particular interest are the inorganic ions, sodium, potassium, calcium, and magnesium. Organic salts may be made with amines, particularly ammonium salts such as mono-, di- and I 1 lI WO 95118120 PCT/US94/13901 7 trialkyl amines or ethanol amines. Salts may also be formed with caffeine, tromethamine and similar molecules. Where there is a nitrogen sufficiently basic as to be capable of forming acid addition salts, such may be formed with any inorganic or organic acids or alkylating agent such as methyl iodide. Preferred salts are those formed with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid.

Any of a number of simple organic acids such as mono-, or tri- acid may also be used.

The compounds of the present invention contain at least one double bond and therefore may have trans and cis (E and Z) isomers, although trans isomers of the but-3-ene double bond are preferred. In adddition, compounds of the present invention may contain two or more chiral centers and therefore exist in enantiomeric and diastereomeric forms. The scope of the present invention is intended to cover all such isomers per se, as well as mixtures of cis and trans mixtures of diastereomers and racemic mixtures of enantiomers (optical isomers) as well.

The preferred compounds of this invention are those of Formula I where Y is phenyl, pyridyl, thienyl or furyl. When Y is phenyl, the preferred compounds where the A-B group is para or meta to the but-3ene-l-enyl chain on the benzene ring.

In the preferred compounds A is (CH 2 n and n is 0,1,or 2; and B is -COOH, an alkali metal salt or organic amine salt thereof. Alternatively, compounds preferred where B is represented by COOR 8 (ester) where R 8 is lower alkyl, CONRgR 10 where Rg and R10 are hydrogen or lower alkyl (amide) CH 2 OH (alcohol),

CH

2

OCOR

11 CH20R 11 where R 11 is lower alkyl; (lower

II

WO 95/18120 PCT/US94/13901 8 alkyl esters and ethers formed with lower alkanol).

Generally speaking, the carboxylic acids esters and amides (B COOH, COOR 8 or CONRgRI 0 are more preferred than the alcohol or its esters (B CH20H or CH20COR 11 With respect to the but-3-ene double bond, substituents about this bond are in the trans (E) configuration in the preferred compounds of this invention. The R6 and R7 substituents preferably are H, or lower alkyl, more preferably methyl or hydrogen.

The R 5 substituent is preferably lower alkyl, most preferably methyl, and is preferably attached to the 2position of the epoxidized cyclohexane ring. The R I

R

4 substituents are preferably H or lower alkyl, and more preferably H or methyl.

Particularly preferred compounds of the invention are shown in Table 1 with reference to Formula 3 and Formula 4: C0W--O2 x Formula 3 WO 95/18120 PCT/US94/13901 9 CO R

O

Formula 4 TABLE 1 Compound No Formula X R 8 position of COOR 8 group 1 3 CH H 4 (para) 2 3 CH H (meta) 3 4 S H n/a* 4 3 N H 3 N C2H5 6 4 S C 2

H

5 n/a* 7 4 O H n/a* n/a not applicable The compounds of this invention may be administered systemically or topically, depending on such considerations as the condition to be treated, need for site-specific treatment, quantity of drug to be administered, and numerous other considerations.

In the treatment of dermatoses, it will generally r -r esqs WO 95118120 PCT/US94/13901 be preferred to administer the drug topically, though in certain cases such as treatment of severe cystic acne or psoriasis, oral administration may also be used. Any common topical formulation such as a solution, suspension, gel, ointment, or salve and the like may be used. Preparation of such topical form lations are well described in the art of pharmaceutical formulations as exemplified, for example, by Remington's Pharmaceutical Science, Edition 17, Mack Publishing Company, Easton, Pennsylvania. For topical application, these compounds could also be administered as a powder or spray, particularly in aerosol form. If the drug is to be administered systemically, it may be confected as a powder, pill, tablet or the like or as a syrup or elixir suitable for oral administration. For intravenous or intraperitoneal administration, the compound will be prepared as a solution or suspension capable of being administered by injection. In certain cases, it may be useful to formulate these by injection. In certain cases, it may be useful to formulate these compounds in suppository form or as extended release formulation for deposit under the skin or intramuscular injection.

Other medicaments can be added to such topical formulation for such secondary purposes as treating skin dryness; providing protection against light; other medications for treating dermatoses; medicaments for preventing infection, reducing irritation, inflammation and the like.

Treatment of dermatoses or any other indications known or discovered to be susceptible to treatment by retinoid-like compounds will be effected by administration of the therapeutically effective dose of a i i rsll 3 EF L -L L 1 WO 95/18120 PCT/US94/13901 11 one or more compounds of the instant invention. A therapeutic concentration will be that concentration which effects reduction of the particular condition, or retards its expansion. In certain instances, the compound potentially may be used in prophylactic manner to prevent onset of a particular condition. A useful therapeutic or prophylactic concentration will vary from condition to condition and in certain instances may vary with the severity of the condition being treated and the patient's susceptibility to treatment.

Accordingly, no single concentration will be uniformly useful, but will require modification depending on the particularities of the disease being treated. Such concentrations can be arrived at through routine experimentation. However, it is anticipated that in the treatment of, for example, acne, or similar dermatoses, that a formulation containing between 0.01 and 1.0 milligrams per milliliter of formulation will constitute a therapeutically effective concentration for total application. If administered systemically, an amount between 0.01 and 5 mg per kg per day of body weight would be expected to effect a therapeutic resulv in the treatment of many diseases for which these compounds are useful.

The retinoid-like activity of these compounds is confirmed through the classic measure of retinoic acid activity involving the effects of retinoic acid on ornithine decarboxylase. The original work on the correlation between retinoic acid and decrease in cell proliferation was done by Verma Boutwell, Cancer Research, 1977, 37,2196-2201. That reference discloses that ornithine decarboxylase (ODC) activity increased precedent to polyamine biosynthesis. It has been A f., WO 95/18120 PCT/US94/13901 12 established elsewhere that increases in polyamine synthesis can be correlated or associated with cellular proliferation. Thus, if ODC activity could be inhibited, cell hyperproliferation could be modulated.

Although all causes for ODC activity increases are unknown, it is known that 12-0-tetradecanoylphorbol-13acetate (TPA) induces ODC activity. Retinoic acid inhibits this induction of ODC activity by TPA. An assay essentially following the procedure set out in Cancer Res: 1662-1670,1975 may be used to demonstrate inhibition of TPA induction of ODC by compounds of this invention. The results of this assay for certain examplary compounds of the invention are shown in Table 2 below.

Table 2 Compound IC 80 (nmol) 1 4.8 3 22.3 4 21 5 1.07 6 16 Synthetic Processes for Preparing Compounds of the Invention The compounds of this invention can be made by the synthetic chemical pathways illustrated here. The synthetic chemist will readily appreciate that the conditions set out here are specific embodiments which can be generalized to any and all of the compounds represented by Formula 1.

0 WO 95/18120 WO 9518120PCT/US94/13901 epoxiLdizing B agent Formula homologs and derivatives Formula 6 Reaction Scheme 1 SUJBSTITUTE SHEET (RUJLE 26) WO 95/18120 PCT/US94/13901 14 In accordance with Reaction Scheme 1 a cyclohexenyl)but-3-ene-l-ynyl]phenyl derivative of Formula 5, which has the desired R 1

R

7 substituents (as defined in connection with Formula 1) and the A-B group (as defined in connection with Formula 1) attached to the phenyl group, is reacted with an epoxidizing agent to yield the epoxide compound of Formula 6. The starting compound of Formula 5 can be obtained in accordance with the disclosure of United States Patent No. 4,739,098 which is expressly incorporated herein by reference. Generally speaking, the reaction of epoxidation is conducted in a secondary alcohol or ether type solvent such as iso-propyl alcohol or diethyl ether, under a protective blanket of inert gas, such as argon, at ambient temperature.

Meta-chloroperoxybenzoic acid (MCPB) and magnesium monoperoxyphthalate (MMPP) serve as examples of preferred epoxidizing agents. The compounds of Formula 6, shown in Reaction Scheme 1, may already be the desired target compounds or may be readily converted into desired target compounds. This is indicated in Reaction Scheme 1 by conversion into "homologs and derivatives", by such steps as salt formation, esterification, desterification, amide formation and the like. These steps relating to chemical transformations of the A-B group, either before or after epoxide formation, as applicable, are further discussed below.

Carboxylic acids are typically esterified by refluxing the acid in a solution of the appropriate alcohol in the presence of an acid catalyst such as sulfuric acid or thionyl chloride. Alternatively, the carboxylic acid can be condensed with the appropriate i 1.

WO 95/18120 PCT/US94/13901 alcohol in the presence of dicyclohexylcarbodiimide and N,N-dimethylaminopyridine. The ester is recovered and purified by conventional means. Acetals and ketals are readily made by the method described in March, "Advanced Organic Chemistry," 2nd Edition, McGraw-Hill Book Company, p 810). Alcohols, aldehydes and ketones all may be protected by forming respectively, ethers and esters, acetals or ketals by known methods such as those described in McOmie, Plenum Publishing Press, 1973 and Protecting Groups, Ed. Greene, John Wiley Sons, 1981.

A means for making compounds where A is (CH 2 n (n is 1 5) is to subject the compounds of Formula 1, (or of Formula 6) where B is an acid or other function, to homologation, using the well known Arndt-Eistert method of homologation, or other known homologation procedures.

Compounds of Formula 1, where A is an alkenyl group having one or more double bonds can be made for example, by having the requisite number of double bonds incorporated into the halogenated aryl or heteroaryl intermediate which is reacted with an ethyne compound in the preparation of the compounds of Formula within the teachings of United States patent No.

4,739,098. Generally speaking, such compounds where A is an unsaturated carbon chain can be obtained by synthetic schemes well known to the practicing organic chemist; for example by Wittig and like reactions, or by introduction of a double bond by elimination of halogen from an alpha-halo-carboxylic acid, ester or like carboxaldehyde. Compounds of Formula 1 where the A group has a triple (acetylenic) bond can be made by using the corresponding aryl or heteroaryl aldehyde WO 95118120 PCTFVS94/13901 16 intermediate. Such intermediate can be obtained by reactions well known in the art, for example, by reaction of a corresponding methyl ketone with strong base, such as lithium diisopropylamide.

The acids and salts derived from compounds of Formula 1 and of Formula 6 are readily obtainable from the corresponding esters. Basic saponification with an alkali metal base will provide the acid. For example, an ester of Formula 1 or of Formula 6 may be dissolved in a polar solvent such as an alkanol, preferably under an inert atmosphere at room temperature, with about a three molar excess of base, for example, potassium hydroxide. The solution is stirred for an extended period of time, between 15 and 20 hours, cooled, acidified and the hydrolysate recovered by conventional means.

The amide may be formed by any appropriate amidation means known in the art from the corresponding esters or carboxylic acids. One way to prepare such compounds is to convert an acid to an acid chloride and then treat that compound with ammonium hydroxide or an appropriate amine. For example, the acid is treated with an alcoholic base solution such as ethanolic KOH (in approximately a 10% molar excess) at room temperature for about 30 minutes. The solvent is removed and the residue taken up in an organic solvent such as diethyl ether, treated with a dialkyl formamide and then a 10-fold excess of oxalyl chloride. This is all effected at a moderately reduced temperature between about -10 degrees and +10 degrees C. The last mentioned solution is then stirred at the reduced temperature for 1-4 hours, preferably 2 hours. Solvent removal provides a residue which is taken up in an i I~ 11~3111 WO 95/18120 PCT/US94/13901 17 inert organic solvent such as benzene, cooled to about 0 degrees C and treated with concentrated ammonium hydroxide. The resulting mixture is stirred at a reduced temperature for 1 4 hours. The product is recovered by conventional means.

Alcohols are made by converting the corresponding acids to the acid chloride with thionyl chloride or other means March, "Advanced Organic Chemistry", 2nd Edition, McGraw-Hill Book Company), then reducing the acid chloride with sodium borohydride (March, Ibid, pg. 1124), which gives the corresponding alcohols.

Alternatively, esters may be reduced with lithium aluminun hydride at reduced temperatures. Alkylating these alcohols with appropriate alky halides under Williamson reaction conditions (March, Ibid, pg. 357) gives the corresponding ethers. These alcohols can be converted to esters by reacting them with appropriate acids in the presence of acid catalysts or dicyclohexylcarbodiimide and dimethylaminopyridine.

Aldehydes can be prepared from the corresponding primary alcohols using mild oxidizing agents such as pyridinium dichromate in methylene chloride (Corey, E.

Schmidt, Tet. Lett., 399, 1979), or dimethyl sulfoxide/oxalyl chloride in methylene chloride (Omura, Swern, Tetrahedron. 1978, 34, 1651).

Ketones can be prepared from an appropriate aldehyde by treating the aldehyde with an alkyl Grignard reagent or similar reagent followed by oxidation.

Acetals or ketals can be prepared from the corresponding aldehyde or ketone by the method described in March, Ibid, p 810.

i I L1 ~lls WO 95/18120 PTU9I3O PCTIUS94/13901 MCPBA or

MMPP

Formula 7 and S derivatives Formula 8 Reaction Scheme 2 SUBStITUTE SHEET (RULE 26)

I

L_ I 1- WO 95/18120 PCT/US94/13901 19 Reaction Scheme 2 illustrates the synthesis of compounds of the invention where, with reference to Formula 1 the Y group is a 5-membered heterocyclic ring, such as thienyl or furyl. The starting material, a compound of Formula 7, is obtained in accordance with the teachings of United States Patent No. 4,927,947, the specification of which is expressly incorporated herein by reference. The compounds of Formula 7 are reacted with an epoxidizing agent, such as metachloroperoxybenzoic acid magnesium monoperoxyphthalate, to yield the compounds of Formula 8. The compounds of Formula 8 may be the desired target compounds, or may be converted into desired target compounds by the transformations discussed in connection with Reaction Scheme 1.

I--r rr 41111 WO 95/18120 WO 9518120PCTIUS94i13901

A-B

MCPBA.

Formula 9 Formula homologs and derivatives REACTION SCHEME 3 WO 95/18120 PCTIUS94/13901 21 Reaction Scheme 3 illustrates the synthesis of compounds of the invention where, with reference to Formula 1 the Y group is a 6-membered heterocyclic ring, such as pyridyl. The starting compounds of Formula 9 for this reaction scheme can also be obtained in accordance with the teachings of United States Patent No. 4,927,947. The compounds of Formula 9 are epoxidized by reaction with meta-chloroperoxybenzoic acid or magnesium monoperoxyphthalate, to yield the compounds of Formula 10. The compounds of Formula may be the desired target compounds, or may be converted into desired target compounds by the transformations discussed in connection with Reaction Scheme 1. This is indicated on the reaction scheme by conversion of compounds of Formula 10 into "homologs and derivatives".

Examples of reagents to be used within the teachings of United States Patent Nos. 4,739,098 and 4,927,947 to obtain starting materials corresponding to compounds of Formula 2, Formula 5, Formula 7 and Formula 9, as applicable, are as follows: ethyl 4-iodobenzoate; ethyl 3-iodobenzoate; ethyl 6-chloronicotinate; ethyl 5-bromo-2-furoate; ethyl 5-bromo-3-furoate; ethyl 5-bromo-2-thiophenecarboxylate; ethyl 5-bromo-3-thiophenecarboxylate; ethyl ethyl 2-bromo-6-pyrazinecarboxylate; ethyl ethyl 2-bromo-6-pyrimidinecarboxylate; ethyl 3-bromo-4-pyridazinecarboxylate;

L,

WO 95/18120 WO 9518 iZO CTIUS94113901 22 ethyl 6-trimethylcyclohex-l'-enyl)but-l-ene-3yne; 1- -dimethylcyclohex-l '-enyl) but-l-ene-3-yne; ,6'-tetramethylcyclohex-l'-enyl)but-lene-3-yne; 1- -pentamethylcyclohex-l'-enyl) butl-ene-3-yne.

Examples of compounds of Formula 2, Formula Formula 7 and Formula 9, as applicable, which can be obtained from the above-noted reagents and are used in the epoxidation reactions disclosed in accordance with the present invention to obtain compounds of Formula 1, Formula 6, Formula 8 and Formula 10 are as follows: ethyl 4-[4 '-(211,6"1,6"-trimethylcyclohex-l-enyl)but-3 '-en- 1 '-ynyl]benzoate; ethyl 3-[4 '(2"1,61 6"-trimethylcyclohex-lenyl) but-3 -ynyl ]benzoate; ethyl 6-[4'-(2"1,6"1,6"-trirnethylcyclohex-lenyl) but-3 -ynyl 3nicotinate; ethyl 5-[4'-(2"1,6"1,6"-,trimethylcyclohex-lenyl) but-3 -ynyl] -2 -furoate; ethyl 5-[4 ,61, 6"1-trimethylcyclohex-lenyl) but-3 -ynyl~thiophene-2-carboxylate; ethyl 2-[4'-(2"1,6"1,6"-trimethylcyclohex-lenyl)but-3 ethyl 2-[4 6"1, 6-trimethylcyclohex-lenyl) but-3 -ynyl]pyrazine-6-carboxylate; ethyl 2-[4'-(2"1,6",6"1-trimethylcyclohex-lenyl)but-3 ethyl 2-[4 6"-trimethylcyclohex-lenyl)but-3 -ynyllpyrimidine-6-carboxylate; WO 95/18120 WO 958120P~US94/139M 23 ethyl 3-14'-(2"1,6"1,6"-trimethylcyciohex-ienyl) but-3 '-en-i '-ynyl]pyridazine-4-carboxylate; ethyl 3-[4'-(2"1,6"1,6"-trimethyicyclohex-ienyl) but-3 '-en-i ethyl 4- 6"-dimethylcyclohex-l-enyl)but-3 en-i' -ynyi 3benzoate; ethyl 3-[4 6"-dimethylcyclohex-l-enyl)but-3 en-i '-ynyl 3benz oate; ethyl 6-[4 '-(6"1,6"1-dimethyicyciohex-l-enyi)but-3 1 0 en-i' -ynyl ]nicotinate; ethyl 5-[4 6"-dimethylcyclohex-l-enyi)but-3 en-i '-ynyl]3-2-furoate; ethyl 5-[4 6"-dimethyicyclohex-l-enyl)but-3 en-i '-ynyl] thiophene-2-carboxylate; ethyl 2-[4 6"-dimethylcyclohex-i-enyi)but-3 en-i ethyl 2-[4 '-(6"1,6"1-dilnethyicyclohex-i-eniyi)but-3 en-i '-ynyl 3pyraz ine-6-carboxyi ate; ethyl 2-[4 6"-dimethylcyclohex-l-enyl)but-3 en-i ethyl 2-[4 6"-dimethyicyciohex-i-enyi)but-3 en-i '-ynyl 3pyrimidine-6-carboxylate; ethyl 3-[4 '-(6"1,6"1-diinethylcyciohex-l-enyi)but-3 en-i '-ynyl]pyridazine-4-carboxylate; ethyl 3-[4 6"-dixethylcyclohex-i-enyl)but-3 en-i '-yny ethyl 4-[4'-(3"1,3"1,6",6"1-tetrarnethylcyciohex-lenyl) but-3 -ynyl]benzoate; ethyl 3-[4'-(3"1,3",6"1,6"1-tetrainethyicyclohex-ienyi)but-3 '-en-l'-ynyllbenzoate; ethyl 6-[4 ,6"1-tetraxnethylcyclohex-lenyl) but-3 '-en-i '-ynyl 3nicotinate; ethyl 5-[4 6"-tetramethylcyclohex-lwo 95/18120 WO 9518120PCT/US94/13901 24 enyl)but-3 -ynyi]-2-furoate; ethyl 5-[4 6" ,6"1-tetrainethylcyciohex-ienyl) but-3 -ynyl] thiophene-2 -carboxyiate; ethyl 2-[4 ,31, 611,6"1-tetramethyicyclohex-lenyl)but-3 '-en-i ethyl 2-[4 6"1, 6-tetramethylcyclohex-ienyl) but-3' -en-i' -ynyi )pyrazine-6-carboxylate; ethyl 2-[4 6",6"1-tetralmethylcyciohex-ienyl) but-3 '-en-i '-ynyl ethyl 2-[4'-(3"1,311,6",6"1-tetrainethylcyclohex-ienyl)but-3'-en-i' -ynyi]pyrimidine-6-carboxyiate; ethyl 3-[4'-(3"1,3",611,6"-tetramethylcyclohex-ienyl) but-3 '-en-i '-yny pyridaz ine-4 -carboxylate; ethyl 3-[4'-(3"1,3",611,6"-tet ramethyicyciohex-lenyl) but-3 '-en-i ethyl 6"1, 6"-pentamethylcyclohex-lenyl) but-3 -yny benzoate; ethyl 3-[4 ,311,3"1,61, 6"-pentainethyicyclohex-lenyl) but-3 '-en-i '-yny benzoate; ethyl 6-[4'-(2"1,311,3"1,61,6"-pentamethyicyciohex-l- (.nyl) but-3 '-en-i '-yny nicotinate; ethyl 6"1, 6"-pentamethylcyclohex-lenyl) but-3 -ynyi] -2-furoate; ethyl 5-[4'-(2"1,3",3"1,6"1,6"-pentamethyicyclohex-lenyi)but-3 -ynyl]thiophene-2-carboxylate; ethyl 2-[4'-(21,311,311,61,611-pentamethyicyclohex-).enyl)but-3 '-en-i ethyl 2-[4'-(2"1,3"1,3"1,61,6"-pentametl-hyicyclohex-lenyi)but-3 '-en-i '-ynyi~pyrazine-6-carboxyiate; ethyl 2-[4'-(2"1,31,311,61,6"1-pentamethylcyclohex-lenyl)but-3 ethyl 2-[4'-(2"1,31,3"1,6"1,6"-pentamethyicyclohex-lenyl) but-3 -ynyi 3pyrixnidine-6-carboxylate; WO 95/18120 PTU9/30 PCT/US94/13901 ethyl 3-[ 41 -(2"1,3"1,311,6",6"-pentamethylcyclohex-lenyl) but-3 -ynyl ]pyridazine-4-carboxylate; ethyl 3-[4 '-(2"1,3",311,6"1,6"-pentamethylcyclohex-lenyl) but-3 -ynyl Examples of compounds of Formula 1, Formula 6, FormulL 8 and Formula 1.0 (as applicable) other than the below described specific examples, which can be made in analogy to the below described specific examples, are: ethyl 4-4-11,1-pxy2 16"1trimethylcyclohexan-.-yi) but-3 -ynyl Jbenzoate; ethyl 3-[4'-(i"1,2"1-epoxy-2"1,61,61"trimethylcyclohexan-l-yl) but-3 -ynyl) benzoate; ethyl 5-[4'-(l"1,2"1-epoxy-2"1,6",6"1trimethylcyclohexan-1-yl) but-3 -ynyl) -2-furoate; ethyl 2-[4'-(l"1,2"1-epoxy-2"1,61, 6"1trimethylcyclohexan-l-yl) but-3 '-en-i '-ynyl carboxylate; ethyl 2-[4'-(l"1,2"1-epoxy-2"1,61,6"1trimethylcyclohexan-1-yl) but-3 '-en-i '-ynyl 3pyrazine-6carboxylate; ethyl 2-[4'-(i"1,2"1-epoxy-2"1,6",6"1trimethylcyclohexan-i-yl) but-3 -ynyl 3pyrimidineethyl 2-[4 '-(l",2"1-epoxy-2"1,61,6"1trimethylcyclohexan-i-yl) but-3 -ynyl 3pyrimidine- 6-carboxylate; ethyl 3-[4'-(l"1,2"1-epoxy-2"1,6",6"1trimethylcyclohexan-l-yl) but-3 -ynyi 3pyridazine- 4-carboxylate; ethyl 2"-epoxy-21, 6"1, 61trimethylcyclohexan-l-yl) but-3 -ynyl 3pyridazineethyl 4-[4 2"-epoxy-6"1, 6"-dimethylcyclohexan- WO 95/18120 WO 9518120PCT[US94/13901 26 1-yi) but-3 '-en-i '-ynyl ]benzoate; ethyl 3-[4 2"-epoxy-61, 6"1-dimethyicyciohexanl-yl) but-3 -ynyi ]benzoate; ethyl 6-[4 2"-epoxy-6" 6"-diinethyicyclohexani-yl) but-3 -ynyi] nicotinate; ethyl 5-[4 21-epoxy-6" 6"-dimethylcyclohexani-yl) but-3 -ynyi) -2-furoate; ethyl 5-[4 ,2"1-epoxy-61, 6"1-dixnethyicyclohexani-yl) but-3 -ynylj thiophene-2-carboxyiate; ethyl 2-[4 '-(i",2"1-epoxy-6"1,6"1-dimethyicyciohexani-yi)but-3 ethyl 2-[4 2"-epoxy-6" 6"-dimethylcyclohexanl-yl)but-3 -ynyi]pyrazine-6-carboxylate; ethyl 2-[4 ,2"1-epoxy-6" 6"-dimethylcyclohexanl-yl)but-3 '-en-i ethyl 2-[4 '-(i",2"1-epoxy-61, 6"1-diinethyicyclohexani-yl)but-3 -ynyl~pyrimidine-6-carboxyiate; ethyl 3-[4 2"-epoxy-61, 6"1-dimethylcyclohexanl-yl)but-3 -ynyi]pyridazine-4-carboxylate; ethyl 3-[4 '-(i",2"1-epoxy-6"1, 6"-dimethylcyciohexani-yl)but-3 '-en-i ethyl 4-[4 '-(i",2"1-epoxy-3"1,3",6"1,611tetramethylcyclohexan-1-yi) but-3 -ynyl~benzoate; ethyl 3-[4'-(l"1,2"1-epoxy-3"1,3"1,61,61"tetramethylcyciohexan-i-yl) but-3 '-en-i '-ynyl )benzoate; ethyl 6-[4 '-(i",2"1-epoxy-3"1,3",61,6"1tetrainethylcyclohexan-i-yl) but-3 ynyi 3nicotinate; ethyl 5-[4'-(l"1,2"1-epoxy-3"1,3",61,6"1tetramethylcyciohexan-i-yi)but-3 '-en-i '-ynyi]-2furoate; ethyl 5-[4'-(i"1,21"-epoxy-3"1,3"1,6",611tetramethylcyciohexan-i-yi) but-3 -ynyl] thiophene- WO 95/18120 WO 9518120PCTIUS94/13901 27 2 -carboxylate; ethyl 2-[4 '-(l",2"1-epoxy-3"1,3"1,61,611tetramethylcyclohexan-l-yl) but-3 -ynyl Ipyrazineethyl 2-[4 '-(l",2"1-epoxy-31, 3"1, 6",6"1tetramethylcyclohexanl-yl)but-3' -en-i' -ynyl]pyrazine-6-carboxylate; ethyl 2-[4 '-(l",2"1-epoxy-3"1,3"1,61,61"tetramethylcyclohexan-l-yl) but-3 '-en-i '-ynyl ]pyrimi- 1 0 ethyl 2-[4'-(i"1,2"1-epoxy-3"1,311,61,6"1tet%-ramethylcyclohexan-l-yl) but-3 '-en-i '-ynyl] pyrimidine-6-carboxylate; ethyl 3-[41-(l"1,2"1-epoxy-31",3"1,61,6"1tetrainethylcyclohexan-l-yl) but-3 '-en-i '-ynyljpyridazine-4-carboxylate; ethyl 3-[4'-(l"1,2"1-epoxy-3"1,3" ,61,6"1tetra1methylcyclohexan-1-yl) but-3 -ynyl ]pyridaethyl 4-[4'-(l"1,2"1-epoxy-2"1,3" ,31, 6" ,6"1pentaxnethylcyciohexan-l-yl) but-3 -ynyl ]benzoate; ethyl 3-[4 2"-epoxy-2" 3" 6"1pentamethyicyclohexan-l-yl) but-3 '-en-i '-ynyl Jbenzoate; ethyl 6-[4'-(l"1,2"1-epoxy-2"1,3"1,3", 61,611- 2 5 pentamethylcyciohexan-l-yi) but-3 I'-en-i' ynyl] nicotinate; ethyl 5-[4'-(l"1,2"1-epoxy-2"1,3"1,3",61,6"1pentamethylcyciohexan-l-yi) but-3 '-en-i '-ynyi] -2furo ate; ethyl 5-[4 ,2"1-epoxy-21, 3"1,3",61",6"1pentamethylcyclohexan-l-yi) but-3 '-en-i '-ynyi] thiophene- 2-carboxylate; ethyl 2-[4 '-(1i,2"1-epoxy-2"1,3",3, 6"1,6"1- WO 95/18120 WO 9518120PCTfUS94/1390 1 28 pentamethylcyclohexan-l-yl) but-3 -vnyl ]pyrazineethyl 2-[4 2"-epoxy-2" 3" 6"1pentamethylcyclohexan-l-yl) but-3 -ynyi Ipyrazine- 6-carboxylate; ethyl 2-[4'-(l"1,2"1-epoxy-2"1,3"1,31,61,6"1pentamethylcyclohexan-l-yl) but-3 ynyi ethyl 2-[4 '-(l",2"1-epoxy-21, 3"1,3"1,6"1, 6"pentamethylcyclohexan-l-yl) but-3 yny pyrimidine-6-carboxyiate; ethyl 3-[4 2"-epoxy-2"1,3"1,3"1,6"1,6"1pentamethylcyciohexan-l-yl) but-3 '-en-i ynyi]pyridazine-4-carboxyiate; ethyl 3-[4'-(l"1,2"1-epoxy-2"1,3"1,31,61,61"pentamethyicyciohexan-i-yl) but-3 ynyi Specific Examples (3E) -4-(l.2-Epooxy-2 6-trimethvlcvclohexanvl)but-3-en-i-vnvl)1benzoic acid (Compound 1) To a suspension of 0.034 g (0.055 mmol) of magnesium xonoperoxyphthaiate (MMPP) and 1 mL isopropyl alcohol was added enough water to just dissolve the solid (5 drops). This solution was added to a solution of 0.029 g (0.10 mmoi) of trimethyl-l-cyciohexenyl) but-3-en-ynyl) ]benzoic acid in 1 mL iso-propyl alcohol and stirred at ambient temperature for 24 hours. The solution was treated with 2 mL of brine solution and extracted with 3 x 10 mL dichioromethane.

The organic extracts were combined and washed with mL saturated aqueous NaCl and then dried (MgSO 4 The solvent was removed in-vacuo and the residue WO 95/18120 WO 9518120PCTIUS94/13901 29 purified by flash chromatography (SiO 2 75:25, hexane:ethyl acetate) to give the title compound as white solid.

PI4R(CDCl 3 6 0.98(3H, l.08(lH, in), 1.14(3H, 1.22 (3H, 1.37-1.55(3H, in), l.79(lH, in), 1.90(111, in), 5.95(111, d, J=15.7Hz), 6.53(111, d, J=15.711z), 7.54(2H1, d, J=8.4Hz), 8.07(2H, d, J=8.4Hz), 11. 3(1H1, brs).

Oxv-2, 6, 6-trimethvlcyclohexanvl'but-3-en-1-ynvl)lbenzoic acid (Compound 2) To a suspension of 0.037 g (0.060 inmol) of magnesium monoperoxyphthalate (MMPP) and 1 mL isopropyl alcohol was added enough water to just dissolve the solid (about 5 drops). This solution was added to a solution of 0.029 g (0.10 iniol) of trimethyl-1-cyclohexenyl)but-3-en-1-ynyl) ]benzoic acid in 1 mL iso-propyl alcohol and stirred at ambient temperature for 24 hours. The solution was treated with 2 mL of brine solution and extracted with 3 x mL dichloromethane.

The organic extracts were combined and washed with mL saturated aqueous NaCi and then dried (MgS0 4 The solvent was removed in-vacua and the residue purified by flash chromatography (SiO 2 75:25, hexane:ethyl acetate) to give the title compound as a white solid.

PMR (CDCl 3 6 0.98(3H1, 1.11(111, mn), 1.14(3H1, 1.22(3H1, 1.38-1.56(3H, in), 1.76(11, in), 1.90(111, in), 5.92(111, d, J=15.7Hz), 6.51(111,d, J=15.7Hz), 7.42(111, d, J=7.911z), 7.45(lH, d, J=7.811z), 7.66(111, d, J=7.8Hz), 8.03(111, d, J=7.911z), -7.60(111, brs).

(3E) (1,2-Epoxy-2,.6,6-trimethylcvclohexanvl)but-3-en-1-nvl)1-2-thiophenecarboxylic acid -SUBSTITUTE SHEET (RULE 26) I I I WO 95/18120 PCT/US94/13901 (Compound 3) To a solution of 0.050 g (0.145 mmol) of ethyl (±)-5-[(3E)-4-(1,2-epoxy-2,6,6-trimethylcyclohexanyl)but-3en-l-ynyl)]-2-thiophenecarboxylate (Compound 6) and 2.32 mL of THF under argon was added 0.580 mL (0.290 mmol) of 0.5 N LiOH. The resulting solution was stirred at 55°C for 3 hours, cooled to room temperature and the THF removed in-vacuo. The aqueous residue was washed with 0.5 mL diethyl ether, the layers separated, and the aqueous layer treated with diethyl ether mL). The 2-phase solution was stirred rapidly and carefully acidified with 0.290 mL of 1N aqueous HCl.

The ether layer was separated quickly and washed with 1 mL saturated aqueous NaCl and then dried (MgSO 4 The solvent was removed in-vacuo to give the title compound as a yellow solid.

PMR (CDC13): 6 0.97(3H, 1.09(1H, 1.14(3H, 1.21(3H, 1.26(1H, 1.44(2H, 1.79(1H, m), 1.89(1H, 5.93(1H, d, J=15.8Hz), 6.53(1H, d, J=15.8Hz), 7.15(1H, d, J=3.9Hz), 7.74(1H, J=3.9Hz), 11.57(lH,brs).

Ethyl(±)-6- [(3E)-4-(l.2-Epoxv-2,6,6-trimethvlcyclohexanyl)but-3-en-l-ynyl)nicotinate (Compound 0.106 g (0.310 mmol) of 50% metachloroperoxybenzoic acid (MCPBA) was added to a solution of 0.1 g (0.310 mmol) of ethyl (2,6,6-trimethyl-l-cyclohexenyl)but-3-en-lynyl)nicotinate (used as a mixture with 0.6 g (0.310 mmol) of ethyl 3-chloronicotinate), in 10 mL of anhydrous diethyl ether under argon was stirred at ambient temperature for 18 hours. The solution was treated with 10 mL of water and extracted with 3 x mL ether.

s~ r Ir -~rl pp WO 95/18120 PTU9/30 PCTIUS94/13901 31 The organic extracts were combined and washed with mL saturated aqueous NaCi and then dried (MgSO 4 The solvent was removed in-vacuo and the residue purified by flas;h chromatography (SiO 2 90:10, hexane:ethyl, acetate) to give the title compound as a yellow solid.

PMR (CDCl 3 6 0.97(3H, l.l0(lH, mn), 1.14(3H, 1.21(3H, 1.40-1.54(3H, mn), 1.43(3H, t, J=7.2Hz), l.78(lH, in), l.90(lH, mn), 4.39(2H, q, J=7.2Hz), 5.96(lH, d, J=15.7Hz), 9.68(lH, d, J=15.7Hz), 7.51(lH, d, J=7.3Hz), 8.27(lH, d, J=2.1, 8.2Hz), 9.l8(lH, d, J=2.8Hz).

(3E) -4-(1,2-Epoxy-2 .6.6-trimethylcyclohexanyl)but--3-en-1-ynyl~jnicotinic acid (Compound 4) To a solution of 0.055 g (0.162 inmol) of ethyl trimethylcyclohexanyl) but-3-en-l-ynyl) nicotinate (Iompound 5) and 2.6 mL of THF under argon was added 0.648 mL (0.324 inmol) of 0.5 N LiCH. The resulting solution was stirred at 55 0 C for 1 hour, cooled to room temperature and the THF removed in vacou. The aquaeous residue was treated with dichloromethane (3 mL), the 2phase solution stirred rapidly, and carefully acidified with 0.310 mL of 1N aqueous HCL.

The organic layer was separated quickly and washed with 1 mL saturated aqueous NaCl and then dried (MgSO 4 The solvent was removed in-vacuo and to give the title compound as a yellow solid.

PNR (CDCl 3 8 0.96(3H, l.05(lH, mn), 1.12(3H, 1.20(3H, l.25(lH, in), 1.44(2H, in), 1.78(11, in), in), 5.96(lH, di, J=15.8H), 6.69(lH, ci, J=15.8H), 7.55(lH, d, J=8.3Hz), 8.38(111, dci, 8.3Hz), 9.31(111, d, J=l.2Hz), 12.62(lH,brs).

WO 95/18120 WO 9518120PCT[US94/13901 32 (3E)-4-(1,2-Epoxv-2,6,6trimethylcvclohexanyl) but-3-en-l-ynvl) 1-2thiophenecarboxylate (Compound 6) 0.288 g (0.838 mmol) of 50% metachloroperoxybenzoic acid (I4CPBA) was added to a solution of 0.250 g (0.761 mmol) of ethyl 6-tr-imethyl-1-cyclohexenyl) but-3-en-l-ynyl) thiophenecarboxylate in 25 mL of anhydrous diethyl ether under argon and stirred at ambient temperature for 18 hours. The solution was treated with 10 mL of water and extracted with 3 x 50 mL ether.

The organic extracts were combined and washed with mL saturated aqueous NaCi and then dried (MgSO 4 The solvent was removed in-vacuo and the residue purified by flash chromatography (SiO 2 95:5, hexane:ethyl acetate) to give the title compound as a yellow solid.

PMR (ODC1 3 6 0.96(3H, l.05(lH, mn), 1.13(3H, 1.20(3H, 1.37(3H, t, J=7.1 Hz), 1.32-1.55(3H, l.78(lH, in), l.91(lH, in), 4.34(2H, q, J=7.lHz), 5.92(lH, d, J=15.6Hz), 6.51(lH, d, J=15.6Hz), 7.12(lH, d, J=4.OHz), 7.65(111, d, (±)-5-r(3E)-4-(1,2-EPoxy-2,6,6- (trimethylcyclohexanvl)but-3-en-l-vnyl) 1-2-furoic acid (Compound 7) To a suspension of 0.141 g (0.228 inmol) of 80% magnesium monoperoxyphthalate (MMPP) and 2 mL iso-propyl alcohol was added enough water to just dissolve the solid (0.3 mL). This solution was added to a solution of 0.054 g (0.190 minol) of 6-trimethyl-l-cyclohexenyl) but-3-en-l-ynyl) 3-2-furoic acid in 1 mL iso-propyl alcohol and stirred at ambient temperature for 48 hours. The solution was treated with 4 mL of brine and extracted with 3 x 20 mL ethyl acetate.

WO 95/18120 WO 9518120PCTIUS94/13901 33 The organic extracts were combined and washed with mL saturated aqueous NaCl and then dried (MgSO 4 The solvent was removed in-vacuo and the residue purified by flash chromatography (Si0 2 50:50, hexane:ethyl acetate) to give the title compound as a yellow solid.

PMR (CDCl 3 0.94(3H,s), l.08(lH, in), 1.11(3H, 1.17(3H, 1.35-1.50(3H, l.73(lH, mn), l.89(lH, 5.89(111, d, J=15.7Hz), 6.57 (1H, d, J=15.7Hz), 6.62(111, d, J=3.611z), 7.25(lH, d, J=3.6Hz), 9.15(111, brs).

Claims

1. A compound of the f -la R R 2 R 6 Y-A-B R 0 R 3 R 4 where R 1 R7 are hydrogen, lower alkyl of 1 6 carbons, or halogen; Y is phenyl, pyridyl, furyl, thienyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl or oxazolyl; A is (CH 2 n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds; B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR 8 CONRgR 10 CH 2 ORI 1 CH 2 OCOR 11 CHO, CH(OR 12 2 CHOR 1 30, -COR 14 CR 14 (OR 11 2 or CR 14 0R 13 0, where R 3 is an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to carbons, or R 8 is phenyl or lower alkylphenyl, R 9 and Ri 0 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R 11 is lower alkyl, phenyl or lower alkylphenyl, R 12 is lower alkyl, R 13 is divalent alkyl radical of 2-5 carbons and R14 is an I I I- WO 95/18120 PCT/US94/13901 alkyl, cycloalkyl or alkenyl group containing 1 to carbons, or a pharmaceutically acceptable salt thereof.

2. A compound of Claim 1 wherein A is (CH 2 )n and n is 0.

3. A compound of Claim 1 wherein B is COOH or a pharmaceutically acceptable salt thereof, or B is COOR 8

4. A compound of Claim 1 wherein R 6 and R 7 are hydrogen.

5. A compound of Claim 1 where R 1 and R2 are methyl.

6. A compound of Claim 1 where R 5 is methyl.

7. A compound of Claim 1 where R3 and R4 are hydrogen.

8. A compound of Claim 1 where the configuration about the double bond in the but-3-ene-l-yne chain is trans.

9. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and one or more compounds set forth in Claim 1 as the active ingredient. A method for treating skin disorders in a mammal which method comprises administering alone or in conjunction with a pharmaceutically acceptable excipient a therapeutically effective amount of one or more compounds set forth in Claim 1.

11. A compound of the formula Ilrrl 1~4 s ~ea psq~SII-~-rul-~-~p q~ Is I C- I~ WO 95/18120 PCTfUS94/13901 36 1? Y-(CH) -B where RI R 5 are hydrogen or lower alkyl; Y is phenyl, pyridyl, furyl, or thienyl; n is 0 5; and B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COORg, CONRgRg 1 CH 2 0R 11 CH 2 OCOR 11 CHO, CH(OR 12 2 CHOR 13 0, -COR 14 CR 14 (OR 12 2 or CR 14 0R 13 0, where R 8 is an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to carbons, or R 8 is phenyl or lower alkylphenyl, R 9 and Ri 0 independently are hydrogen, an alkyl group of 1 to carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R 11 is lower alkyl, phenyl or lower alkylphenyl, R 12 is lower alkyl, R 13 is divalent alkyl radical of 2-5 carbons and R14 is an alkyl, cycloalkyl or alkenyl group containing 1 to carbons, or a pharmaceutically acceptable salt thereof.

12. A compound of Claim 11 where Y is phenyl.

13. A compound of Claim 12 where R 3 and R4 are hydrogen.

14. A compound of Claim of Claim 13 where R 5 is methyl, and is attached to the 2 position of the g II_~ I~ WO 95/18120 PCT/US94/13901 37 cyclohexane ring. A compound of Claim 14 where n is 0.

16. A compound of Claim 15 where B is COOH, a pharmaceutically acceptable salt thereof, COOR 8 or CONR 9 R 1 0 o

17. A compound of Claim 16 where the configuration about the double bond in the but-3-ene-l- yne chain is trans.

18. A compound of Claim 17 where B is COOH, a pharmaceutically acceptable salt thereof, or COOC 2 H 5

19. A compound of Claim 18 where the B group is attached to the 4 position of the phenyl ring. A compound of Claim 18 where the B group is attached to the 3 position of the phenyl ring.

21. A compound of Claim 11 where Y is pyridyl.

22. A compound of Claim 21 where R 3 and R, are hydrogen.

23. A compound of Claim of Claim 22 where R 5 is methyl, and is attached to the 2 position of the cyclohexane ring.

24. A compound of Claim 23 where n is 0. A compound of Claim 24 where B is COOP, a pharmaceutically acceptable salt thereof, COORg or CONR 9 R 10

26. A compound of Claim 25 where the configuration about the double bond in the but-3-ene-l- yne chain is trans.

27. A compound of Claim 26 where B is COOH, a pharmaceutically acceptable salt thereof, or COOC 2 H 5 i0 28. A compound of Claim 27 where the B group is attached to the 5 position of the pyridine ring.

29. A compound of Claim 11 where Y is thienyl. A compound of Claim 29 where R 3 and R4 are s' 7 IP 1M WO 95/18120 PCT/US94/13901 38 hydrogen.

31. A compound of Claim of Claim 30 where R 5 is methyl, and is attached to the 2 position of the cyclohexane ring.

32. A compound of Claim 31 where n is 0.

33. L compound of Claim 32 where B is COOH, a pharmaceutically acceptable salt thereof, COOR 8 or CONR 9 R 10

34. A compound of Claim 33 where the configuration about he double bond in the but-3-ene-l- yne chain is trans. A compound of Claim 34 where B is COOH, a pharmaceutically acceptable salt thereof, or COOC 2 H 5

36. A compound of Claim 35 where the B group is attached to the 5 position of the thiophene ring.

37. A compound of Claim 11 where Y is thienyl.

38. A compound of Claim 37 where R3 and R4 are hydrogen.

39. A compound of Claim of Claim 38 where Rg is methyl, and is attached to the 2 position of the cyclohexane ring. A compound of Claim 39 where n is 0.

41. A compound of Claim 40 where B is COOH, a pharmaceutically acc-etable salt thereof, COOR 8 or CONR 9 RI 0

42. A compound of Claim 31 where the configuration about the double bond in the but-3-ene-l- yne chain is trans.

43. A compound of Claim 42 where B is COOH, a pharmaceutically acceptable salt thereof, or COOC 2 H 5

44. A compound of Claim 43 where the B group is attached to the 5 position of the thiophene ring. -r INTERNATIONAL SEARCH REPORT It,...onal Aican No PCT/US 94/13901onppon No PCT/US 94/13901 A. CLASSIFICATION OF SUBJECT MATTER IPC 6 C07D303/38 C070409/06 C070401/06 C070407/06 C070303/10 A61K31/44 A61K31/34 A61K31/38 A61K31/335 According to International Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classfication symbols) IPC 6 C070 Documentation searched other than mmum documentation to the extent that such documents are included in the fields searched Electronic data base consulted dunng the inm ~z.ional search (name of data base and, where practical, search term used) C. DOCUMENTS CONSIDERED TO BE RELEVANT Category Citation of document, with indicaton, where appropnate, of the relevant passages Relevant to claim No. A WO,A,93 21146 (LIGAND PHARMACEUTICALS INC) 1-44 28 October 1993 see abstract; claim A EP,A,O 265 069 (ALLERGAN INC) 27 April 1-44 1988 cited in the application see the whole document I Further documents are listed in the continuation of box C. J Patent family members are listed in annex. Special catesones of cited documents: later document published after the iternational filing date or prnonty date and not in conflict with the application but A" document defining the general state of the art which is not cted to understand the principle or theory underlying the considered to be of particular relevance invenuon earlier document but published on or after the international X document of particular relevance; the claimed invention filing date cannot be considered novel or cannot be considered to document which may throw doubt on pnonty claim(s) or involve an inventive step when the document is taken alone which is cited to establish the publication date of another document of particular relevance; the claimed invention citation or other special reason (as specified) cannot be considered to involve an inventive step when the "0 document referring to an oral disclosure, ue, exhibition or document is combined with one or more other such docu. other means ments, such combination being obvious to a person skilled document published pnor to the international filing date but in the art. later than the pnonty date claimed document member of the same patent family Date of the actual completion of the internatonal search Date of mailing of the international search report 31 March 1995 26. 04, 9 Name and mailing address of the ISA Authorized officer European Patent Office, P.B. 5818 Patentlaan 2 NL 2280 HV Rijswi]k Tel. (+31-70) 340.2040, Tx. 31 651 eponi, ai sdor, Fax: (+31-70) 340-3016 or, Form PCT/ISA/210 (second sheet) (July 1992) I LI INTERNATIONAL SEARCH REPORT Inteinational application No, PCT/US 94/ 13901 Box I Observations where certain claims were found unsearchable (Continuation of item 1 of first sheet) This international search report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons: 1. Claims Nos.: because they relate to subject matter not required to be searched by this Authority, namely: Although claim 10 is directed to a method of treatment of (diagnostic method practised on) the human/animal body, the search has been carried out and based on the alleged effects of the compound/composition. 2. U Claims Nos.: becw-e they relate to parts of the international application that do not comply with the prescribed requirements to such an extent that no meaningful international search can be carried out, specifically: 3. Claims Nos.: because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a). Box 11 Observations where unity of invention is lacking (Continuation of item 2 of first sheet) This International Searching Authority found multiple inventions in this international application, as follows: 1. O As all required additional search fees were umely paid by the applicant, this international search report covers all searchable claims. 2. l As all searchable claims could be searches without effort justifying an additional fee, this Authority did not invite payment of any additional fee. 3. O As only some of the required additional search fees were timely paid by the applicant, this international search report covers only those claims for which fees were paid, sp-cifically claims Nos.: 4. No required additional search fees were timely paid by the applicant. Consequently, this international search report is restricted to the invention first mentioned in the claims; it is covered by claims Nos.: Remark on Protest 7 The additional search fees were accompanied by the applicant's protest. IO No protest accompanied the payment of additional search fees. Form PCTIISA/210 (continuation of first sheet (July 1992) I INTJER~NATJINAL SE1ARCHl REP RTI( Intel. .onnl Application No PCT/US 94/13901 Patent document Publication IPatent family I Publication cited in search report date Imember(s) Idate WO-A-9321146 28-10-93 AU-B- 4118893 18-11-93 AU-B- 5586894 15-08-94 AU-B- 6225894 15-08-94 CA-A- 2133587 28-10-93 EP-A- 0637297 08-02-95 NO-A- 943943 21-12-94 WO-A- 9415901 21-07-94 WO-A- 9504036 09-02-95 WO-A- 9415902 21-07-94 EP-A-0265069 27-04-88 US-A- 4739098 19-04-88 AU-B- 602919 01-11-90 AU-A- 7886187 24-03-88 CA-A- 1329620 17-05-94 IE-B- 60614 27-07-94 JP-A- 63101360 06-05-88 Form PCT/ISA1210 (patent Aunily annex) (July 1992)